Sepsis & Septic Shock

1. Sepsis &Septic Shock Mario M. Panaligan, MD, FPCP, FPSMID

2. REFERENCES • Harrison’s Principles of Internal Medicine, 17th ed • Severe Sepsis and Septic Shock (Chapter 265, pp. 1695-1702) • Treatment and Prophylaxis of Bacterial Infections (Chapter 127, pp. 851-864) • Antiviral Chemotherapy, Excluding Antiretroviral Drugs (Chapter 171, pp. 1087-1095) • Diagnosis and Treatment of Fungal Infection (Chapter 191, pp. 1242-1244) • Agents Used to Treat Parasitic Infections (Chapter 201, pp. 120-1275) • Dellinger RP, Levy MM, Carlet JM, et al. Surviving sepsis campaign: International guidelines for management of severe sepsis and septic shock: 2008. Critical Care Med 2008; 36 (1): 296-327

3. “Sepsis is a disease of medical progress…”

4. SEPSIS • 10th leading cause of death in the US • Estimated 751, 000 cases of severe sepsis each year in the US • With a mortality rate of 28.6% and an annual cost of US$16.7 billion • Worldwide, 18 million cases of severe sepsis occur annually, killing approximately 1400 people each day and incurring a healthcare cost of US$9.4 billion in Europe alone Nguyen HB, Rivers EP. The Clinical Practice of Early Goal-Directed Therapy in Severe Sepsis and Septic Shock. Adv Sepsis 2005;4(4):126–33.

5. Sepsis • Prospective observational study at UP-PGH in 1998 involving 1,270 patients • Prevalence rate: 25% • Mortality rate: 34% • Sepsis-related: 77% • Septic shock: 42% Alejandria MM, Phil J Microbiol Infec Dis, 2000

7. Risk Factors for Progressing to Severe Sepsis and Poor Outcome Alberti C et al. Am J Respir Crit Care Med 2005; 171: 461 Alberti C et al. Am J Respir Crit Care Med 2003; 168: 77

8. Bacteremia Other Fungemia Trauma INFECTION SIRS SEPSIS Parasitemia Burns Viremia Others Pancreatitis

9. Infection/Trauma Sepsis Severe Sepsis SIRS • A clinical response arisingfrom a nonspecific insult, including 2 of the following: • Temperature >38oC or <36oC • HR >90 beats/min • Respiratory rate >20/min or PaCO2 < 32 mmHg • WBC count >12,000/mm3or <4,000/mm3 or >10% immature neutrophils SIRS = systemic inflammatory response syndrome. Bone et al. Chest. 1992;101:1644.

10. Infection/Trauma Sepsis Severe Sepsis SIRS • A clinical response arisingfrom a nonspecific insult, including 2 of the following: • Temperature >38oC or <36oC • HR >90 beats/min • Respiratory rate >20/min or PaCO2 < 32 mmHg • WBC count >12,000/mm3or<4,000/mm3 or >10% immature neutrophils • SIRS with a presumed or confirmed infectious process SIRS = systemic inflammatory response syndrome. Bone et al. Chest. 1992;101:1644.

11. Shock Infection/Trauma Sepsis Severe Sepsis SIRS • Sepsis with ≥1 sign of organ failure • Cardiovascular (refractory hypotension) • Renal • Respiratory • Hepatic • Hematologic • CNS • Unexplained metabolic acidosis Bone et al. Chest. 1992;101:1644; Wheeler and Bernard. N Engl J Med. 1999;340:207.

12. SEPTIC SHOCK Severe Sepsis WITH Hypoperfusion abnormalities AND Persistent Hypotension Despite adequate fluid resuscitation Bone RC, Chest 1992;101:1644-1655 Rangel-Frausto M, JAMA, 1995; 273: 117

13. MULTIPLE ORGAN DYSFUNCTION SYNDROME (MODS) SEPTIC SHOCK PLUS Altered organ function such that homeostasis cannot be maintained without intervention Bone RC, Chest 1992;101:1644-1655 Rangel-Frausto M, JAMA, 1995; 273: 117

14. SEPSIS SEVERE SEPSIS SEPSIS-INDUCED HYPOTENSION SEPTIC SHOCK Multiple Organ Dysfunction Syndrome (MODS) Sepsis: A Disease Continuum

15. Pathogenesis Trigger (organism-derived, e.g. endotoxin) Release of tumor necrosis factor α / other proinflammatory cytokines Inflammatory cascade Hypothalamus Capillary endothelial cell Vessel wall Fever Tachycardia Tachypnea Neutrophil migration Platelet adherence DIC Depletion of intravascular vol Nitric oxide synthesis Vasodilatation Cellular hypoxia Death Organ dysfunction/hypoperfusion Hypotension

16. Primary Fever and chills Hypothermia Hyperventilation Skin lesions Change in mental status Complications Hypotension Bleeding Leukopenia Organ failure Lungs: cyanosis, acidosis Kidney: oliguria, acidosis Heat: congestive heart failure Signs and symptoms suggestive of sepsis

17. Management of Patients with Sepsis

18. DIAGNOSTIC WORK-UP • HISTORY • Thorough PE • Search for source/s of infection • Identify signs of systemic organ dysfunction • Diagnostic tests • Ancillary laboratory exams • ABGs, Renal and liver function tests, CBC • Appropriate microbiologic examinations • Specimens are obtained before antibiotic therapy • Consideration for immediate administration of antibiotic/s Dellinger RP, et al. Crit Care Med, 2008

19. Biomarkers of sepsis? • Utility? • Ability to influence or affect a diagnostic or therapeutic decision • To identify a subgroup of patients who are more likely to benefit from a given intervention and to maximize clinical benefit of that therapy  To predict response to therapy

20. Biomarkers of sepsis? The PIRO Model Marshall JC, Current Infect Dis Reports 2006, 8: 351 Levy MM, Intensive Care Med 2003, 29: 530

21. Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock: 2008 Dellinger RP, Levy MM, Carlet JM, et al. Critical Care Med 2008; 34: 17-60.

22. Issues in Improving Outcome of Patients with Severe Sepsis • The surviving sepsis guidelines • Early goal-directed therapy (EGDT) • Low-dose intravenous steroids • Strict blood glucose level control • Recombinant activated protein C • Appropriate early antimicrobial therapy Dellinger RP et al. Crit Care Med 2008; 32, Suppl

23. GRADE System of Recommendations • Quality of Evidence (Grade) • A (High quality): RCT • B (Moderate): Downgraded RCT or upgraded observational studies • C (Low): Well done observational studies • D (Very Low): Case series or expert opinion • Strength of Recommendation • 1: Strong • 2: Weak

24. CURRENT MANAGEMENT OF SEVERE SEPSIS AND SEPTIC SHOCK • Immediate stabilization procedures • Definitive therapeutic intervention Dellinger RP, et al. Crit Care Med, 2008

25. Initial Resuscitation Supportive Management Diagnosis Management Recognition

26. INITIAL RESUSCITATION

27. INITIAL RESUSCITATION • First 6 hours • Begin resuscitation immediately in patients with hypotension or elevated serum lactate >4mmol/l; do not delay pending ICU admission (1C) • Resuscitation goals: (1C) • Central venous pressure (CVP) 8 - 12 mm Hg • Mean arterial pressure > 65 mm Hg • Urine output > 0.5 mL/kg/hr • Central venous (superior vena cava) oxygen saturation > 70%, or mixed venous > 65% Dellinger RP, et al. Crit Care Med, 2008

28. IMMEDIATE STABILIZATION • Reversal of life-threatening abnormalities • Special attention for the ABCs • Airway protection for patients with depressed level of consciousness • MV support • Circulatory support to optimize organ perfusion • Aggressive fluid management • Inotropics or vasopressors when necessary • Hemodynamic monitoring • Urine output Dellinger RP, et al. Crit Care Med, 2008

29. FLUID THERAPY • Fluid-resuscitate using crystalloids or colloids (1B) • Target a CVP of > 8 mmHg (>12 mmHg if mechanically ventilated) (1C) • Use a fluid challenge technique while associated with hemodynamic improvement (1D) • Give fluid challenges of 1000 ml of crystalloids or 300-500 ml of colloids over 30 minutes • Rate of fluid administration should be reduced if cardiac filling pressures increase without concurrent hemodynamic improvement (1D) Dellinger RP, et al. Crit Care Med, 2008

30. VASOPRESSORS / INOTROPIC SUPPORT • Maintain MAP > 65mmHg (1C) • Norepinephrine (NE) or dopamine (DOP) centrally administered are the initial vasopressors of choice (1C) • Epinephrine, phenylephrine or vasopressin should not be administered as the initial vasopressor in septic shock (2C) • Use epinephrine as the first alternative agent in septic shock when BP is poorly responsive to NE or DOP (2B) Dellinger RP, et al. Crit Care Med, 2008

31. VASOPRESSORS / INOTROPIC SUPPORT • Use dobutamine (DOB) in patients with myocardial dysfunction as supported by elevated cardiac filling pressures and low cardiac output (1C) • Do not increase cardiac index (CI) to predetermined supranormal levels (1B) • Do not use low-dose dopamine for renal protection (1A) • In patients requiring vasopressors, insert an arterial catheter as soon as practical (1D) Dellinger RP, et al. Crit Care Med, 2008

32. DIAGNOSIS AND MANAGEMENT

33. DIAGNOSIS • Obtain appropriate cultures before starting antibiotics provided this does not significantly delay antimicrobial administration (1C) • Obtain two or more blood cultures (BCs) • One or more BCs should be percutaneous • One BC from each vascular access device in place > 48 hours • Culture other sites as clinically indicated • Perform imaging studies promptly in order to confirm; and • Sample any source of infection; if safe to do so Dellinger RP, et al. Crit Care Med, 2008

34. Antimicrobial Therapy • Mainstay of treatment for patients with infection and sepsis Dellinger RP, et al. Crit Care Med, 2008

35. EMPIRIC ANTIMICROBIAL THERAPY • Broad-spectrum • Selection based on the presumed site of infection and the likely pathogens involved • Gram stain result if available • Local susceptibility patterns • To be started within an hour after performance of important microbiologic exams • Other factors to consider include • Host’s immune status • Allergies • Renal or hepatic dysfunction Dellinger RP, et al. Crit Care Med, 2008

36. Definitive Antibiotic Therapy • Pathogen-directed • Pharmacokinetic – pharmacodynamic properties of the antibiotic • Site of Infection Dellinger RP, et al. Crit Care Med, 2008

37. PREDICTORS OF POOR OUTCOME • Age • Severity of the underlying condition • Presence of complications at the onset of treatment • Grade (severity) of bacteremia • Source of infection • Inappropriate antimicrobial therapy Mandell GL, Principles of Infectious Diseases, 2005

38. Impact of Inadequate Antibiotic Treatment on All-Cause Mortality P<0.001 • All-cause mortality: more than twice as high among patients who received inadequate antibiotic treatment compared to those who received adequate antibiotic treatment Inadequate Antibiotic Treatment (n=169 patients) Adequate Antibiotic Treatment (n=486 patients) Adapted from MH Kollef et al. Inadequate antimicrobial treatment of infections: A risk factor for hospital mortality. Chest 1999; 115: 462-474

39. Impact of Inadequate Antimicrobial Treatment on Infection-related Mortality P<0.001 • Infection-related mortality: more than twice as high among patients who received inadequate antibiotic treatment compared to those who received adequate antibiotic treatment Inadequate Antibiotic Treatment (n=169 patients) Adequate Antibiotic Treatment (n=486 patients) Adapted from MH Kollef et al. Inadequate antimicrobial treatment of infections: A risk factor for hospital mortality. Chest 1999; 115: 462-474

40. Non-modifiable Presence of malignancy Severe underlying condition (High MSOF and MPM scores) Gram-negative bacteremia Modifiable Inappropriate antimicrobial therapy Use of alternative antibiotics Nosocomial acquisition of infection Risk factors for mortality Alejandria MM, Phil J Microbiol Infect Dis, 2000

41. Timing of antimicrobial therapy • Review of 3 cohorts of adult patients with septic shock (N=2731) • 58% community-acquired; 42% nosocomial • Documented infection seen in 78% • 50% received effective antimicrobial treatment within 6 hours of documented hypotension • Overall mortality was 56% • Survival rate: 82.7% in patients receiving effective antimicrobials within 30 minutes VS 42% in patients receiving antimicrobials 6 hours after the onset of septic shock • Mean 7.6% decrease in survival for every hour of delay in the initiation of antibiotic therapy Kumar A, Crit Care Med 2006; 34: 1589

42. Source Control • Definite identification of site of infection • Drainage of an abscess or local focus of infection • Debridement of infected necrotic tissue • Removal of a potentially infected device • Definitive control of a source of ongoing microbial contamination Dellinger RP, et al. Crit Care Med, 2008

43. Source Control

44. Supportive Management Adjunctive Measures

45. Glucose Control • Use of IV insulin to control hyperglycemia in patients with severe sepsis following stabilization in the ICU (1B) • Aim to keep blood glucose < 8.3 mmol/L (150 mg/dl) using a validated protocol for insulin dose adjustment (2C) • Provide a glucose calorie source and monitor blood glucose values every 1-2 hrs (4 hrs when stable) in patients receiving IV insulin (1C) Dellinger RP, et al. Crit Care Med, 2008

46. Renal Replacement and Bicarbonate Therapy • Intermittent hemodialysis (HD) and continuous veno-venous hemofiltration (CVVH) are considered equivalent (2B) • CVVH offers easier management in hemodynamically unstable patients (2D) • Do not use bicarbonate therapy for the purpose of improving hemodynamics or reducing vasopressor requirements when treating hypoperfusion-induced lactic acidemia with pH > 7.15 (1B) Dellinger RP, et al. Crit Care Med, 2008

47. Use of Steroids • Do not use steroids to treat sepsis in the absence of shock unless the patient’s endocrine or hydrocortisone history warrants it (1D) • IV hydrocortisone for adult septic shock when hypotension remains poorly responsive to adequate fluid resuscitation and vasopressors (2C) • Hydrocortisone dose is usually < 300 mg/day (1A) • Hydrocortisone is preferred to dexamethasone (2B) • Fludrocortisone (50 ug orally OD) may be included if an alternative is being used which lacks significant mineralocorticoid activity (2C) Dellinger RP, et al. Crit Care Med, 2008

48. Use of Steroids • Meta-analysis of 16 trials (n=2063) on the effects of corticosteroids on mortality in patients with severe sepsis or septic shock • Analysis of 15 trials (n=2022) • No reduction of all cause mortality in 28 days (RR=0.92, 95% CI 0.75, 1.14) • Subgroup analysis of 5 trials (long duration > 5 days and low dose corticosteroid therapy) • All cause mortality: RR=0.8, 95% CI 0.67, 0.95) Annane D, BMJ Aug 2004

49. Use of Steroids • ACTH stimulation test is not recommended to identify the subset of adults with septic shock who should receive hydrocortisone (2B) • Steroid therapy may be weaned once vasopressors are no longer required (2D) Dellinger RP, et al. Crit Care Med, 2008

50. DVT prophylaxis • Use either low dose unfractionated heparin (UFH) or low-molecular weight heparin (LMWH), unless contraindicated (1A) • Use a mechanical prophylactic device such as compression stockings or an intermittent compression device, when heparin is contraindicated (1A) • Use a combination of pharmacologic and mechanical therapy for patients who are at very high risk for DVT (2C) • In patients at very high risk, LMWH should be used rather than UFH (2C) Dellinger RP, et al. Crit Care Med, 2008